Diagnostic Accuracy and Interpretation of Urine Drug

2
Diagnostic Accuracy and Interpretation of
Urine Drug Testing for Pain Patients:
An Evidence-Based Approach
Amadeo Pesce1, Cameron West1, Kathy Egan-City1 and William Clarke2
1Millennium
2Johns
Research Institute,
Hopkins School of Medicine,
USA
1. Introduction
Pain is a complex disease. The complexities and co-morbidities of this disease include
depression, anxiety, addiction, and other psychological diagnoses that lead to difficulties in
management and aberrant behavior such as not taking medications as prescribed, taking
additional medications, or illicit drugs. In the effort to provide the highest standard of care
for their patients, pain physicians are required to continually assess patients for addiction
and, if necessary, refer them to addictionologists for additional treatment (Chou et al., 2009).
1.1 Chronic opioid therapy
In this chapter we will refer to pain patients as those persons being treated with chronic
opioid therapy for non-cancer-related pain. It is this patient population that has been
associated with opiate abuse and diversion, and therefore monitoring these patients for
drug use in a manner analogous to therapeutic drug monitoring is necessary. One of the
most frequent complaints by patients seeing pain physicians is back pain, which is often
associated with failed back surgery (Manchikanti et al., 2004; Michna et al., 2007). Currently
opiate medications are one of the treatments of choice used by physicians to provide pain
relief. These medications can induce euphoria as well as pain relief; because of this, opiates
are frequently abused by this population, as well as the general population (National Survey
on Drug Use and Health: Detailed Tables - Prevalence Estimates, Standard Errors, P Values,
and Sample Sizes, 1995-2006; Webster & Dove, 2007). Additionally, these medications are
associated with physical as well as psychological dependence and can pose addiction risks
(Webster & Dove, 2007).
1.2 Pain treatment
One of the treatments of choice for chronic pain involves strong medications such as
opioids, as well as additional or adjuvant medications (Chou et al., 2009; Trescot et al., 2006).
Side effects of opioids include sedation, dizziness, nausea, vomiting, and constipation.
Living day to day with any or all of these symptoms is challenging at the least and is
compounded by the underlying pain these patients suffer from. Naturally, patients often
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Toxicity and Drug Testing
attempt to minimize the side effects by taking less of the medication when side effects are
particularly debilitating or unpleasant. “Chronic pain patients often adjust their dose of
prescribed medication in response to changing levels of activity with no malicious or
maladaptive intent. Although they may state that their pattern of use of medications is
stable, this is often a statement made ‘‘on average’’ rather than a precise pattern of use. This
is particularly evident with short-acting medications used in the treatment of breakthrough
pain.” (Gourlay & Heit, 2010b)
UDT is used to give confidence to both the physician and the patient that the patient is
following the medication regimen and is therefore getting the most benefit from their
treatment. In addition, the side effects of these medications often result in their misuse,
underuse, and/or mixing of medications that are not prescribed (Manchikanti et al., 2004).
This can also result in the social problems of abuse, misuse, or diversion of these
medications. These factors require of pain physicians that they be particularly attentive to
their prescribing practices. Adding to the complexity of managing pain patients is the fact
that these medications are controlled substances and cannot be purchased over the counter,
and so have high street value (Katz et al., 2003; National Prescription Drug Threat
Assesment, 2009). This in turn requires of the physician that he or she determine whether
patients under their care are compliant with their medication regime, binging on their
medications, or diverting them for financial gain (Manchikanti et al., 2005, 2006a, 2006b).
1.3 Complications of pain treatment
Further compounding the situation, alcohol use is of major concern to the physician because
alcohol-drug interactions can cause morbidity (Harmful Interactions: Mixing Alcohol with
Medicines, 2007). Although physicians prohibit patient alcohol use during treatment with
opiates or benzodiazepines, verbal contracts are commonly broken and therefore alcohol use
must be monitored with (UDT) to manage the high risk of alcohol-drug reactions and
mortality (Chou et al., 2009; Trescot et al., 2006). In addition, for reasons involving
inadequate pain control, sleep deprivation, and psychological pathology, this patient
population commonly takes other medications not prescribed by treating physicians as well
as illicit drugs (Manchikanti et al., 2005, 2006a, 2006b). To respond to these potential
problems, physicians traditionally relied upon behavioral assessment and pill counts to aid
them in making treatment decisions. UDT has augmented these tools by providing
physicians with objective, scientifically measurable outcomes to help them make decisions
(Gourlay et al., 2010; Hammett-Stabler & Webster, 2008; Nafziger & Bertino, 2009; Reisfield
et al., 2007). A detailed protocol of how to appropriately prescribe these controlled
substances for this population is discussed in the book Universal Precautions, by Gourlay and
Heit (Gourlay et al., 2005).
2. Urine drug testing
Traditionally, UDT has been associated with forensic testing, often referred to as workplace
testing, to detect illicit drug use in employees. Workplace UDT has traditionally focused on
identifying use of abused drugs including amphetamines (methamphetamine), cocaine,
marijuana, phencyclidine (PCP), and heroin (opiates) (Federal Register - Mandatory
Guidelines and Proposed Revisions to Mandatory Guidelines for Federal Workplace Drug
Testing Programs [Federal Register], 2004). This type of testing is oriented toward
determining positive results; that is, identifying the presence of an illicit substance. The
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Diagnostic Accuracy and Interpretation
of Urine Drug Testing for Pain Patients: An Evidence-Based Approach
27
reasoning behind this focus is obvious; a positive result for a prohibited substance is a cause
for a consequence such as job dismissal (Federal Register, 2004). Testing for these drugs
usually follows scheduled guidelines established by the Substance Abuse and Mental
Health Services Administration (SAMHSA) (Federal Register, 2004). Analytically, the testing
involves qualitative immunoassay screening followed by confirmation by mass
spectrometry. Testing for patients on chronic opioid therapy is a different paradigm as both
positive and negative results are important. It also requires assays that are more sensitive
and can determine both the parent drug and one or more of its metabolites.
2.1 Immunoassays
Immunoassays are tests that are based on the ability of an antibody to bind with a drug
(Feldkamp, 2010). Antibodies are made in such a way that they bind with a specific drug, such
as morphine. In one approach, manufacturers of point of care (POC) devices embed test strips
with antibodies and install them in devices designed to interact with urine specimens
(Amedica Drug Screen Test Cup). A urine specimen with the drug in it (in this example,
morphine) will displace the drug-indicator molecule on the test strip causing the morphine
drug indicator line to disappear or change color. These test strips are then visually inspected
by the person administering the test. The absence or presence of a line or the change in color,
such as on a home pregnancy test, indicates whether the result is positive or negative. The
immunoassay antibody binding reaction can be measured in other, more sophisticated ways
than using test strips, such as reference laboratory analytical instruments (Olympus Au640
Product Information; Siemens V-Twin Analyzer Product Information; Thermo Fisher Mgc-240
Analyzer Product Information). However, the fundamental property of immunoassays is
always the binding reaction of the antibody to the test drug (analyte).
2.2 Limitations of immunoassay
The qualitative immunoassay model of testing is only a partial UDT solution for the pain
population (Gourlay et al., 2010; Hammett-Stabler & Webster, 2008; Nafziger & Bertino,
2009; Reisfield et al., 2007). There are a number of reasons for this. First, doctors treating
patients for pain are concerned with negative as well as positive results. This is because a
negative result can mean that a patient is not taking a prescribed medication. Second,
workplace UDT assays do not fit the clinical medication regimen used in the treatment of
pain patients and do not take into account the variable dosing often employed by pain
patients as they try to balance their need for pain relief against the side effects of these
medications (Gourlay & Heit, 2010a). In analytical terms this means that the cutoff for
detection and quantitation (concentration of drug present) must be low enough to capture
minimal use of the drug. Thirdly, the physicians need to have an exact indication of the
medications the patients are taking. For example, a positive opiate test does not indicate
whether the patient is on codeine, hydrocodone, morphine, or hydromorphone. That is, it
measures the class not the particular drug. Each of these are specific medications the
physician may choose to treat the patient with, so in order to establish compliance it is
necessary to determine exactly which medication has been ingested and assure the patient is
not taking additional opiates which could create an unsafe situation (Cone et al., 2008).
Finally, if an immunoassay screening method is used, the antibody must detect all drugs of
that particular class. Recent advances in designing opiate and benzodiazepine classes of
drugs have resulted in agents which do not react well with the traditional antibodies. and
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Toxicity and Drug Testing
are used in much lower concentrations than the earlier-designed drugs (Fraser, 2001). This
complicates identification of these new agents by immunoassay.
3. Drugs observed in pain patients
Table 1 lists both licit and illicit drugs as well as alcohol and the frequency observed in the
pain patient population tested by Millennium Laboratories. These observations are similar
to those reported by Cone (Cone et al., 2008). The medications most commonly found in the
urine of this population are clearly hydrocodone and oxycodone, followed by morphine and
hydromorphone; codeine is not frequently prescribed for this population. Benzodiazepines
are the next most prescribed group. Other opioid medications such as fentanyl, meperidine,
tramadol, and propoxyphene are less frequently used. Use of the muscle relaxants
carisoprodol is commonly seen. Marijuana is by far the most prevalent among the illicit
drugs, followed by cocaine and methamphetamine. From the table it is clear that alcohol use
is about 10% as measured by the presence of alcohol’s metabolites ethyl glucuronide (EtG)
and ethyl sulfate (EtS) (Crews et al., 2011a; Dahl et al., 2002; Helander & Beck, 2005;
Helander et al., 1996; Schmitt et al., 1997; Stephanson et al., 2002; Wojcik & Hawthorne, 2007;
Wurst et al., 2006; Wurst et al., 2004). These data show that in order to provide appropriate
monitoring and decrease risk and mortality for this population, a broad test menu is needed.
These same drugs are often abused and frequently found to be present though they had not
been prescribed by the treating physician. Table 2 shows the frequency of these nonprescribed drugs in the pain patient population.
3.1 Need for urine drug testing
Many physicians prescribing opioids for non-cancer pain patients follow guidelines
established by the American Pain Society (Chou et al., 2009). These guidelines specify the
regular or periodic use of UDT as a component of treatment, including administering UDT
upon assessing potential risk for substance abuse, misuse or addiction (Atluri & Sudarshan,
2003; Ives et al., 2006; Madras et al., 2009). Guidelines also suggest that doctors use UDT to
monitor patient adherence to prescribed treatments and further state that periodic UDT is
warranted because “the therapeutic benefits of these medications are not static and can be
affected by changes in the underlying pain condition, coexisting disease, or in psychological
or social circumstances” (Chou et al., 2009). In observation of these recommendations, many
physicians use POC devices to obtain a real time, in-office assessment of patient compliance,
illicit drug use and possible diversion (Manchikanti et al., 2006b, 2010).
3.2 Point of care testing
As mentioned previously, these POC devices are qualitative immunoassays that test for
various drug classes as well as a few specific drugs. A typical POC device can measure 12
drugs or drug classes (Amedica Drug Screen Test Cup). The most commonly monitored
agents are barbiturates, benzodiazepines, opiates, oxycodone, propoxyphene, methadone,
tricyclic antidepressants and the illicit drugs methamphetamine, marijuana, cocaine,
methylenedioxymethamphetamine (MDMA), and phencyclidine (PCP). The physicians use
these screens to immediately detect adherence to regimen or non-adherence to the
prescribed drug therapy. At that point they can elicit a more complete drug history, initiate
a conversation assessing the need for additional medications not prescribed, or confront the
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Diagnostic Accuracy and Interpretation
of Urine Drug Testing for Pain Patients: An Evidence-Based Approach
29
Alcohol
Ethyl Glucuronide
Ethyl Sulfate
Ethanol (Screen)
Total Specimens Tested
N
%
Mean
Median
Range
Cutoff
Positive Positive
(ng/mL)
(ng/mL)
(ng/mL)
(ng/mL)
10,594
10.0%
8,602
81.2%
59,827.9
7,220.1
500.47 - 5,942,830
500
6,644
62.7%
18,660.7
3,546.1
500.17 - 1,565,150
500
2,410
22.7% 735.1 mg/dL 68.6 mg/dL 20 - 151,316 mg/dL 20 mg/dL
106,014
Amphetamines
Amphetamine
Methamphetamine
MDA
MDMA
Total Specimens Tested
7,005
6,045
1,178
961
74
167,533
4.2%
86.3%
16.8%
13.7%
1.1%
8,471.2
18,217.8
1,771.1
5,328.2
2,790.2
3,263.8
844.5
1,260.6
100.31 - 409,816
105.12 - 453,763
101 - 416,68.9
120.14 - 40,395.3
100
100
100
100
Barbiturates
Barbiturates (Screen)
Total Specimens Tested
4,797
4,797
133,032
3.6%
100.0%
927.8
904.0
200 - 15,886
200
Benzodiazepines
α-Hydroxyalprazolam
Oxazepam
7-Amino-Clonazepam
Temazepam
Nordiazepam
Lorazepam
Total Specimens Tested
60,160
26,954
18,475
16,466
15,647
12,758
6,390
168,980
35.6%
44.8%
30.7%
27.4%
26.0%
21.2%
10.6%
479.9
2,036.0
674.6
5,552.3
693.9
1,583.1
177.3
617.4
287.0
851.9
281.5
681.2
20 - 55,249.1
40 - 203,128
20.01 - 47,501.7
50 - 752,950
40 - 25,864.3
40.09 - 63,170.8
20
40
20
50
40
40
Buprenorphine
Buprenorphine
Norbuprenorphine
Total Specimens Tested
6,308
5,841
4,237
104,972
6.0%
92.6%
67.2%
313.0
639.8
75.1
279.0
10.01 - 58,691.5
20 - 13,615.1
10
20
Cannabinoids
cTHC
Total Specimens Tested
11,752
11,752
104,453
11.3%
100.0%
579.6
153.1
15 - 25,960.3
15
Carisoprodol
Meprobamate
Carisoprodol
Total Specimens Tested
13,302
13,188
5,379
80,990
16.4%
99.1%
40.4%
36,884.0
2,931.9
16,190.5
455.0
100.18 - 1,244,200
100.1 - 648,442
100
100
Cocaine
Cocaine metabolite
Total Specimens Tested
4,951
4,951
166,501
3.0%
100.0%
12,372.5
627.1
50.05 - 342,160
50
Drug Class
Table 1. Drug and Metabolite Prevalence, Positivity, and Concentrations. N = 184,049 patient
specimens. Test dates: 10/01/09–4/29/10.
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Toxicity and Drug Testing
N
%
Positive Positive
Fentanyl
13,141
14.1%
Norfentanyl
11,589
88.2%
Fentanyl
9,283
70.6%
Total Specimens Tested 93,526
Drug Class
Mean
(ng/mL)
Median
(ng/mL)
Range
(ng/mL)
Cutoff
(ng/mL)
626.8
109.4
236.6
36.1
8 - 47,354.9
2 - 33,050.7
8
2
Meperidine
Normeperidine
Meperidine
Total Specimens Tested
6,310
4,247
2,522
86,344
7.3%
67.3%
40.0%
1,456.3
34,321.8
339.5
13,533.4
50 - 276,993
50.18 - 616,862
50
50
Methadone
EDDP
Methadone
Total Specimens Tested
12,415
12,109
11,792
113,073
11.0%
97.5%
95.0%
7,871.9
5,265.1
4,117.3
2,409.4
100.05 - 251,835
100.11 - 260,433
100
100
Opiates
Hydrocodone
Hydromorphone
Oxymorphone
Oxycodone
Morphine
Codeine
6-Acetylmorphine
Total Specimens Tested
116,683
59,346
51,205
49,688
41,603
21,400
3,686
465
180,487
64.6%
50.9%
43.9%
42.6%
35.7%
18.3%
3.2%
0.4%
2,564.4
836.0
5,760.2
11,207.3
29,611.8
4,752.0
1,108.8
859.9
240.4
1,298.6
2,124.5
9,600.3
828.4
275.7
50 - 477,876
50 - 204,633
50 - 1,512,220
50 - 5,947,380
50.06 - 1,995,940
50.01 - 233,036
10.01 - 24,069.1
50
50
50
50
50
50
10
Phencyclidine
Phencyclidine
Total Specimens Tested
23
23
104,137
0.02%
100.0%
539.4
87.5
10.89 - 3,718.53
10
Propoxyphene
Norpropoxyphene
Propoxyphene
Total Specimens Tested
6,397
6,395
2,780
133,992
4.8%
100.0%
43.5%
5,524.3
1,919.5
2,026.9
583.6
100 - 167,037
100 - 178,006
100
100
Tapentadol
Tapentadol
Total Specimens Tested
277
277
66,797
0.4%
100.0%
11,557.1
6,870.3
52.05 - 492,895
50
Tramadol
Tramadol
Total Specimens Tested
6,521
6,521
54,111
12.1%
100.0%
19,288.0
8,191.4
100 - 601,928
100
Table 1. (continued). Drug and Metabolite Prevalence, Positivity, and Concentrations. N =
184,049 patient specimens. Test dates: 10/01/09–4/29/10.
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Diagnostic Accuracy and Interpretation
of Urine Drug Testing for Pain Patients: An Evidence-Based Approach
DRUG CATEGORY
Benzodiazepine
Illicit Drugs
Natural and Semi-Synthetic Opioids
Other
Stimulants
Synthetic Opioids
TOTALS
Total Creatinine Tests
Total RADAR C Positives
% POSITIVE
Benzodiazepine
7-Amino-Clonazepam
Alpha-Hydroxyalprazolam
Lorazepam
Nordiazepam
Oxazepam
Temazepam
Illicit Drugs
6-MAM (Heroin metabolite)
Cocaine metabolite
Methamphetamine
MDMA
cTHC (Marijuana metabolite)
Phencyclidine
Natural and Semi-Synthetic Opioids
Buprenorphine
Codeine
Hydrocodone
Hydromorphone
Morphine
Norbuprenorphine
Oxycodone
Oxymorphone
Other
Carisoprodol
Ethyl Glucuronide
Ethyl Sulfate
Meprobamate
Stimulants
Amphetamine
Synthetic Opioids
EDDP (Methadone metabolite)
Fentanyl
Meperidine
Methadone
Norfentanyl
Normeperidine
Norpropoxyphene
Propoxyphene
Tapentadol
Tramadol
OCCURRENCES
14,559
6,769
13,241
11,514
954
4,379
51,416
69,888
51,416
73.57%
14,559
3,864
5,543
1,079
1,907
1,803
363
6,769
165
1,710
320
17
4,546
11
13,241
809
692
5,138
1,789
1,317
73
2,618
805
11,514
735
5,320
4,820
639
954
954
4,379
1,381
729
29
271
204
55
898
25
17
770
31
% of TOTAL
28.32%
13.17%
25.75%
22.39%
1.86%
8.52%
100.00%
Table 2. Incidence of Non-prescribed Use of Prescription Medications and Illicit Drugs.
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Toxicity and Drug Testing
patient about illicit drug use. Point of care devices are extremely useful because they
provide physicians with immediate information, particularly on initial patient intake. Of
course, like many CLIA-waived (or simple) test devices, they do have limitations, inasmuch
as they require that a person visually inspect them in order to interpret the results. For this
reason as well as the fact that these units are not 100% accurate, manufacturers of POC
devices recommend that doctors not confront patients without first confirming the POC
results (Table 3) (Amedica Drug Screen Test Cup). Table 3 lists a number of known drugs or
agents that cause false positive results in POC immunoassays. In contrast with POC
immunoassay tests, which only show a positive or negative result, laboratory-based
immunoassays are often semi-quantitative (Feldkamp, 2010). This means that a positive
result for morphine will also indicate approximately how much morphine is in the
specimen. These immunoassays have quality control and proficiency testing surveys that
make the results more objective and reliable than those obtained using POC devices
(American Proficiency Institute 2011 Catalog of Programs, 2011; College of American
Pathologists 2011 Surveys and Anatomic Pathology Education Programs, 2011).
POCT Kit
Drug or Drug
Target Drugs1
Abbreviation
Class
Marijuana and Marinol
THC
Marijuana
(contains THC),
COC
Cocaine
Cocaine
Codeine, morphine,
hydrocodone,
OPI3002
Opiates
hydromorphone. Also, poppy
seeds that contain morphine.
AMP
Amphetamines
MET
Methamphetamine
PCP
Phencyclidine
MDMA
Methylenedioxymetham
phetamine
BAR
Barbiturates
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Compounds That May
Cause A False Positive1
Prilosec, Protonix ,
efavirenz, NSAIDs
Unknown/Infrequent
Oxycodone
Phenylpropanolamine,
Amphetamine, Adderall.
ephedrine,
Occasionally: benzphetamine, pseudoephedrine,
selegiline, Vicks Nasal Inhaler4 ranitidine,
phentermine
Adderal,
Methamphetamine.
phenylpropanolamine,
Occasionally: benzphetamine,
ephedrine,
selegilene, Vicks Nasal
pseudoephedrine,
Inhaler4
ranitidine, phentermine
Venlafaxine,
Phencyclidine
dextromethorphan,
diphenhydramine
Phenylpropanolamine,
Methylenedioxyephedrine,
methamphetamine
pseudoephedrine,
ranitidine, phentermine
Butalbital, phenobarbital,
secobarbital, amobarbital and Unknown/Infrequent
other barbiturates
Diagnostic Accuracy and Interpretation
of Urine Drug Testing for Pain Patients: An Evidence-Based Approach
BZO
MTD
TCA
OXY3
Oxazepam, nordiazepam,
Benzodiaze- temazepam, alprazolam and
pines
other benzodiazepines to
varying degrees
Methadone Methadone
Amitriptyline, nortriptyline,
Tricyclic
imipramine, desipramine,
Antidepresdoxepin and other tricyclics to
sants
varying degrees.
Oxycodone
33
Oxaprozin, sertaline
Verapamil, quetiapine
Cyclobenzaprine,
carbamazepine,
diphenhydramine
Codeine, morphine,
Oxycodone and oxymorphone hydrocodone and
hydromorphone
Table 3. False Positive Results: Immunoassay Cross Reactants.
1 While most immunoassays are highly selective for their target compounds, cross reactive compounds
and adulterants, particularly when present at high concentrations may result in a false positive.
Additional cross reactants have been reported and cross reactivity may vary between immunoassay
manufacturers and lot to lot. The manufacturers of point of care test devices recommend that positive
results should be confirmed by mass spectrometry.
2 OPI300 is an assay to detect codeine, morphine, hydrocodone and hydromorphone. Oxycodone may
give a positive at higher concentrations.
3 OXY is an assay to detect Oxycodone. Other opiates, esp. codeine, morphine, hydrocodone and
hydromorphone may give a positive result at higher concentrations.
4 Adderall contains amphetamine. Benzphetamine (Didrex) is metabolized to d-amphetamine and dmethamphetamine. Selegiline (Eldepryl) is metabolized to l-amphetamine and l-methamphetamine.
Vick’s Inhaler contains l-methamphetamine.
3.3 Determining appropriate UDT cutoffs
Sensitivity of detection currently used in many immunoassays may not be appropriate for
the pain patient. This is because manufacturers set cutoffs for assays to identify overdose in
emergency unit settings (Fraser & Zamecnik, 2003; Fraser, 2001; Hattab et al., 2000; Wingert,
1997). There is a need to establish appropriate cutoffs for patients on clinical doses of their
medications rather than the high concentrations encountered in overdose situations.
Specifically, studies have been conducted that better identify the appropriate cutoff for the
pain patient population (Pesce et al., 2011).
One definition of appropriate cutoff levels is one that captures 97.5% or more of the
population on a specific drug (Pesce et al., 2011). An example of the importance of setting
appropriate cutoffs is for the drug clonazepam (West et al., 2010b). When measured by
immunoassay using a nominal cutoff of 200 ng/mL, only 28% of the patients on the drug
were determined to be compliant. When the same samples were measured by LC-MS/MS
technique using a cutoff of 200 ng/mL, the group was found to be 70% compliant. Finally,
when the LC-MS/MS cutoff was lowered to 40 ng/mL the group was 87% compliant. This
study showed that first the immunoassay was insensitive in that the nominal 200 ng/mL
cutoff did not apply to clonazepam, and second, a lower cutoff was needed to appropriately
categorize compliance. Other studies have shown the need for lower cutoffs for pain
medications (Mikel et al., 2009; Pesce et al., 2010a). As the consequences to the patient of
dismissal from a practice can be very large and even life-changing (e.g., loss of insurance,
loss of job or income), it is essential that physicians do not unjustifiably dismiss even a
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Toxicity and Drug Testing
single patient who is compliant with their medication regimens. This can be avoided by
using appropriate cutoffs.
In an attempt to better define appropriate cutoffs for the pain patient population, the
quantitative urine drug test results were examined for the prescription medications listed in
Table 4. Using the criterion that the cutoffs should capture 97.5% of the examined
population and employing the LC-MS/MS cutoffs listed in Table 4 showed it was possible
to meet this standard (Pesce et al., 2011). One limitation of this approach is that the time
after last dose and the dose itself were not known for these subjects. Regardless of the
limitations of the study, the lower cutoffs provide results that can clearly identify
compliance more accurately than other methods.
Drug
Analytical
Cutoff (ng/mL)
Lower 2.5%
Estimated New
CR Normalized Cutoff
Cutoff (Raw, ng/mL)
(µg/g creatinine)
7-Amino-Clonazepam
10
19
15
Alpha-Hydroxyalprazolam
10
15
11
Amphetamine
50
76
59
Buprenorphine
5
7
5
Carisoprodol
50
56
35
Codeine
25
29
15
Fentanyl
1
2
2
Hydrocodone
25
41
31
Hydromorphone
25
34
26
Lorazepam
20
30
25
Meperidine
25
88
28
Meprobamate
50
92
113
Methadone
50
89
74
Morphine
25
59
52
Oxycodone
25
45
46
Oxymorphone
25
44
38
Propoxyphene
50
60
42
Tapentadol
25
42
58
Tramadol
50
147
70
Table 4. Medication Cutoff Values. Modified with permission from Pesce et al., 2011.
As stated earlier, illicit drug use is common in this population (Madras et al., 2009;
Schuckman et al., 2008). It stands to reason that identifying the appropriate illicit drug
cutoffs for UDT is equally important. Using the same criterion as stated above, cutoffs for
marijuana, cocaine, and methamphetamine have also been determined (Table 5) (West et al.,
2011a). The lowering of these illicit drug cutoffs consistent with the latest SAMHSA
guidelines in which the cocaine and amphetamine cutoffs were lowered to capture more
illicit drug users (Federal Register, 2004).
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Drug
35
Lower 2.5%
Raw
CR Normalized
(ng/mL)
(ng/mg CR)
Cocaine
29.6
17
Marijuana
9.5
6.2
Methamphetamine
56.1
33.5
Table 5. Illicit Drug Cutoff Values. Modified with permission from West et al., 2011a.
3.4 Confirmatory testing: mass spectrometry
Physicians dealing with pain patients not following the treatment plan or using illicit or
non-prescribed medications, have difficulty with these situations (Jung & Reidenberg, 2007).
The doctor must be absolutely confident that the test data from both the POC and laboratory
conducting further testing is correct. By having positive results obtained in their offices as
well as confirmatory laboratory data, physicians can confidently discuss expectations and
behavioral changes with patients. Questions about laboratory mix-up of specimens or
laboratory error can be dismissed.
Many laboratories performing UDT on the pain patient population typically test specimens
by immunoassay and then follow this with confirmation by mass spectrometry (Cone et al.,
2008). Mass spectrometry is an analytical technique that separates molecules based on their
weight (mass) and fragmentation pattern. Identification is based on the fact that each drug
has a specific mass and breakdown in the same way that each person has a specific
fingerprint. A mass spectrometry instrument is usually coupled to a chromatographic
column, in which the test drug, for example morphine, is separated from other components
in the urine before submitting the sample into the mass spectrometer. The mass
spectrometer identifies the test drug by its position in the chromatogram, the specific weight
of the molecule, and by its fragmentation pattern. This technology is virtually foolproof.
Mass spectrometry techniques are divided into two methods: gas chromatography-mass
spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LCMS/MS). Of the two, the newer LC-MS/MS is considered the gold standard, for reasons we
will describe later (Siuzdak, 2006).
In cases where the physician wants the results immediately (within hours), confirmatory
mass-spectrometry methods used at the most modern diagnostic laboratories provide
results within 24-30 hours. As stated above, the major limitations of immunoassays are
inappropriate cutoffs (sensitivity), varying specificity for individual drugs, and crossreactivity with other agents producing both false-negative and false-positive results
(Manchikanti et al., 2008). The term cross reactivity is used to describe the reaction of an
antibody with a chemical that is not the original immunizing drug. The reaction is poor
because the affinity is much worse than the original drug. By poor we mean that at the same
concentration of the original drug the test compound does not bind as well. However, as the
concentration of the test compound is increased it eventually saturates the antibody binding
site giving a positive test result.
3.5 Test menu requirement
As mentioned earlier a broader clinical laboratory UDT menu is necessary to accurately
monitor the pain patient population. Smaller hospitals as well as physician offices cannot
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meet this requirement. One reason for this is that immunoassays require separate
analytical channels for each assay and this limits the number of tests a smaller laboratory
may have in its menu (Olympus Au640 Product Information; Siemens V-Twin Analyzer
Product Information; Thermo Fisher Mgc-240 Analyzer Product Information). Another
reason is that certain drug tests may not exist for the laboratory’s specific instruments,
and the addition of another instrument is financially prohibitive, particularly if that
instrument is a mass spectrometer (Agilent Technologies, Inc.). Many physicians treating
the pain patient population send specimens to reference laboratories specifically designed
to provide the required test menu to meet these needs. Tests for new drugs (i.e.,
tapentadol) (Nucynta - Tapentadol, 2010) or new illicit substances (i.e., K2, spice)
(Sobolevsky et al., 2010; Vardakou et al., 2010) encountered in the pain patient population
can be rapidly set up and validated on LC-MS/MS instrumentation. Therefore, this
analytical technique is supplementing screening by immunoassay. Because of the
limitations of immunoassays, confirmatory testing is essential for accurate clinical
assessment of medication usage. With confirmatory testing, physicians have specific
evidence of what medications a patient is or isn’t taking. This assures the doctor that he or
she is not discharging a patient inappropriately, and that care is appropriate and not
limited.. The laboratories with the most advanced technology can eliminate the
immunoassay step saving both the patient and the insurer money.
3.6 Mass spectrometry as the gold standard for testing
At this point in time, mass spectrometry is considered the method of choice for UDT
analysis in pain management. This is because mass spectrometry offers the
chromatographic separation and mass fragmentation patterns that are specific for the test
medications such as opiates and benzodiazepines (Mohsin et al., 2007). In addition, this
analytic approach uses isotope dilution to quantify the amount of drug in the urine
specimen; isotope dilution is considered the gold standard for determining how much of a
drug is in a specimen (quantitation) (Federal Register, 2004). This ability to quantify the
amount of drug in urine has been proposed as a method of detecting drug abuse (Pesce et
al., 2010c). However, it is important to note that it is not possible to relate the quantitative
excretion of a drug to the drug dosage (Nafziger & Bertino, 2009). Quantitation of drugs
using immunoassay technology is problematic, particularly if the antibody reagent cross
reacts with multiple structurally related drugs; if the urine drug sample contains more
than one drug in a class (i.e., hydrocodone and hydromorphone), the antibody reaction
will vary with each drug present in the solution. This means that the assay cannot
distinguish between the two drugs and give a reliable calculation of the amount of either
drug present (Feldkamp, 2010).
Of the two commonly used mass spectrometry methods, LC-MS/MS offers several
advantages over GC-MS (Mikel et al., 2010). These include the ability to discriminate a
larger number of drugs in each test run, the very small amount of urine specimen required
(as little as 25 microliters, or one drop), and the ability to use a sample that is neither
derivatized nor extracted. This in turn has made possible the analysis of hundreds of urine
specimens per day for a single mass spectrometer. Advances in the automated handling of
specimens and bar coding allow for the accurate processing of thousands of samples per
day. This method of analysis can provide physicians with results more rapidly than by GCMS (Mikel et al., 2010).
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4. Interpretation of UDT results
The accurate interpretation of test results requires an understanding of the usefulness and
limitations of immunoassays (Gourlay et al., 2010; Hammett-Stabler & Webster, 2008;
Manchikanti et al., 2010; Nafziger & Bertino, 2009; Reisfield et al., 2007), a knowledge of opiate
metabolism, and awareness of the expected ratios of the parent drug and its metabolites in
urine (Reisfield et al., 2007). In addition, small amount of impurities in medications detectable
by mass spectrometry can complicate the interpretation of UDT results. For example, codeine
is present in morphine preparations and hydrocodone is present in oxycodone preparations
(Evans et al., 2009; West et al., 2009, 2011b). Physicians who aren’t aware of the presence of
these impurities may wrongly dismiss a patient because he or she tested positive for codeine
or hydrocodone when it was not prescribed. The presence of both parent drug and its
metabolite in a urine sample readily measured by mass spectrometry can reassure the
physician that the patient is taking the medication and that it is being metabolized
appropriately. Also, for some drugs such as carisoprodol, fentanyl, or buprenorphine, only the
metabolite may be observed. It is imperative that physicians prescribing these medications use
a reference laboratory that is able to measure both the parent drug and its corresponding
metabolite and be able to present interpretive results for the physician (Heltsley et al., 2010).
Creatinine is a metabolic breakdown product that is present in urine. The amount of
creatinine excreted into urine is nearly constant for any individual. Reference laboratories
calculate the amount of drug excreted per gram of creatinine, which allows the monitoring
of excreted medication or illicit drug over time. This information is useful to physicians in
certain circumstances because some drugs, such as nordiazepam remain in the system long
after a person stops taking them. A UDT result that is not corrected for creatinine may show
that the patient is more positive for the drug than on a previous test, even though the
patient has in fact stopped taking it. Except for changes in the patient’s renal status, or loss
from adipose tissue due to dieting, this conflicting result may be due to the second urine
being more concentrated than the first. A creatinine-corrected value will correct for a
patient’s hydration on the day of the test and show a decrease in the amount of
nordiazepam in the urine, thus supporting the patient’s claim that he or she has stopped
taking the drug. It is important that reference laboratories not only provide creatininecorrected results but that they give doctors or staff help in interpreting the data (Cone et al.,
2009). It is also important for the physician to know if a patient has attempted to obscure
UDT results by diluting a urine specimen. To accomplish this, he or she must have a grasp
of creatinine and specific gravity UDT validity tests (Wu, 2001). Laboratory staff who
interface with clients should provide this information when questions arise.
5. Monitoring ethanol use in pain patients
As stated earlier, alcohol (ethanol) use among pain patients is a significant problem because
of the risk for drug-drug interaction with opioid medication. For doctors to understand UDT
ethanol results, it is essential that they understand ethanol metabolism and the formation of
the ethanol byproducts ethyl glucuronide and ethyl sulfate (Crews et al., 2011a; Crews et al.,
2011b; Dahl et al., 2002; Helander & Beck, 2005; Helander et al., 1996; Rosano & Lin, 2008;
Schmitt et al., 1997; Stephanson et al., 2002; Wojcik & Hawthorne, 2007; Wurst et al., 2006;
Wurst et al., 2004). This is because false positive ethanol results can result from fermentation
of glucose from diabetic patient samples (Crews et al., 2011b). Crews et al. reported that
about 1/3 of the ethanol positive samples were due to fermentation. Misinterpretation of
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Toxicity and Drug Testing
these results can have grave consequences as doctors may establish a contract with a patient
that he or she abstain from any alcohol use while being treated with opioid medication;
therefore, a positive finding for alcohol use can result in dismissal from the practice (Federal
Register, 2004).
6. When to use UDT
Urine drug testing must be tailored to fit the pain patient’s clinical history. For the intake visit,
the patient is advised as to the necessity for UDT and is typically requested to provide a urine
specimen. If the patient fails to do this, he or she may be immediately dismissed from the
practice. In some practices, the urine specimen is tested by a POC device at the time of the
appointment and the results are compared to the patient reported history. If necessary,
discrepancies are discussed. As a matter of course, a portion of the POC urine sample is sent to
the reference laboratory to confirm the POC test results, test for additional medications, and, at
the discretion of the physician, to test for the prescribed medications, non-prescribed
medications and illicit drugs at lower cutoff levels than those provided by the POC test.
For many established pain patients, quarterly or semi-annual UDT is considered
appropriate. It is best if this is done on a random basis. The strongest recommendation for
doing UDT is adding additional medications to the regimen or changing medications. Urine
drug testing may also be administered if a patient changes their behavior or exhibits
addiction tendencies such as complaining of running out of medications early (Chou et al.,
2009; Trescot et al., 2006). Testing may be conducted as frequently as every office visit for
some patients who exhibit unusual behavior, have a history of abuse, or if illicit or nonprescription drugs were found to be present on a previous test. Gourlay, D. & Heit, H.
(2010a).
7. Purposes and costs of UDT
As stated earlier, the purpose of UDT (as well as the relative costs) may be broken down
into three components: testing prescribed medications for compliance; testing for nonprescribed medications; and testing for illicit drugs. At the time when the forensic model of
drug testing was instituted the vast majority of people who died from drugs died from the
use of illicit drugs. At this point in time more people die from prescription medications than
by illicit drugs (Hall et al., 2008; Krausz et al., 1996; Okie, 2010). There are now 13 or more
classes of drugs that are used to treat pain. Pain patients are on an average using three of
these drugs (Kuehn, 2007; Okie, 2010). Therefore, for every 100 patients, 300 confirmations
by mass spectroscopy are required. This is more than a 100-fold increase in the number of
tests needed to serve this patient population compared to workplace testing. This represents
a radical change in UDT model from the forensic model used at the time when the purpose
of drug testing was to root out the one or two percent of drug-using professional drivers. It
is important that legislators and payors for UDT services understand the shift from the
forensic UDT model to the clinical model. Currently the insurance reimbursement codes and
categories do not accurately reflect the costs associated with these new clinical drug testing
requirements (Cpt Current Procedural Technology, 2010).
7.1 Cost effectiveness of UDT
It is also important to discuss the cost-effectiveness of UDT. The National Institute on Drug
Abuse (NIDA) states that the cost of not treating an addict is $56,000/year. An example of
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effective treatment for heroin addiction is the methadone maintenance program, which has an
average cost of $4,700/per patient/per year (Principles of Drug Addiction Treatment: A
Research-Based Guide, 2009). Based on these figures, every dollar invested in drug treatment
programs yields a return of about 12 times this amount. The goal then should be detecting
untreated drug abuse. Urine drug testing helps accomplish this goal.
There are two aspects of drug abuse in the pain patient population; one is the use of illicit
drugs, and the other more prevalent aspect is abuse of the prescribed and non-prescribed
medications. Combined, these two facets of abuse may approach 20-30% of the patients on
chronic opioid therapy. Using this percentage of patients and factoring the $56,000/patient
cost, this means that on average each of these patients may actually be costing society and
insurers $16,800 more annually than what is estimated by only calculating costs of office visits
and medications. If clinical UDT is performed 2-4 times per year for each patient reimbursed at
$500 per UDT, this represents a cost of $1000-$2000 per patient per year. This is in contrast to
the $16,800 referenced above. It seems clear that using UDT to detect these patients should
significantly reduce the cost of care as well as the costs to society (Wall et al., 2000).
7.2 Social costs of drug abuse
In light of the fact that providing the highest standard of care is one of the basic tenets of the
medical profession, it is important to note that several studies have shown that untreated
opioid-abusing patients have significantly higher societal cost (Wall et al., 2000) and
mortality rate (between 2 and 10 times) than the comparative general population (Hall et al.,
2008; Oyefeso et al., 1999). Based on this data alone, the use of UDT should be justified for
pain patients.
8. Conclusions
8.1 When and how to test
Pain is a complex disease and chronic opioid therapy is one of the treatments of choice.
Urine drug testing is one of the ways to measure patient adherence to the treatment
regimen. At the intake office visit it is important for the physician to be able to make
immediate assessment of the patient to validate their reported history and to determine the
overt presence of illicit drugs or non-prescribed medications. Either a POC device or inoffice immunoassay analyzer should be used for this purpose. A portion of the patient’s
urine specimen should be sent to a reference laboratory for analysis using lower cutoffs and
a much extended test menu such as those listed in Tables 1 and 2. As stated earlier, this will
give the physician further confidence that the patient’s history is valid and provide
measurable evidence for informed clinical decision making. In addition, alcohol use, which
cannot easily be detected by the POC devices, can be identified as a risk factor.
8.2 Ongoing testing
At subsequent visits UDT will provide the physician with evidence of patient compliance
with prescribed medications (West et al., 2010a) and eliminate the potential for abuse of
non-prescribed medications or illicit drugs (Pesce et al., 2010b). For this purpose, depending
upon clinical judgment, the test menu does not have to be quite as extensive. Tests for
rarely-observed illicit drugs such as MDMA and PCP may not be included. Similarly, tests
for rarely-prescribed or removed medications such as propoxyphene may not be included. If
intake visit UDT showed that the patient was observed to be taking a non-prescribed
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Toxicity and Drug Testing
medication or illicit drug then subsequent visit UDT’s should include tests for those agents.
Because of the potential for morbidity from alcohol-medication interactions, it may be
necessary to continue to monitor certain patients for ethanol and its metabolites.
8.3 Minimum analytical requirements
When monitoring for opioid medication compliance, the testing method should be able to
differentiate between codeine, morphine, hydrocodone, norhydrocodone, and
hydromorphone. The test should also be able to differentiate between oxycodone,
noroxycodone, and oxymorphone. This will allow the physician to determine that the opiate
the patient is taking is in fact the one being prescribed and that the patient is metabolizing
the medication properly (Pesce et al., 2010a). A similar case can be made for the testing of
benzodiazepines. The method should be able to detect at low concentrations and
differentiate between alpha-hydroxyalprazolam, 7-aminoclonazepam, lorazepam,
nordiazepam, temazepam, and oxazepam. This will allow the doctor to see that the patient
is taking the prescribed benzodiazepine and allay any concerns about doctor shopping.
Frequency of UDT should be based on the physician’s observations of the patient’s behavior
as well as suggested guidelines. For those patients whose behavior is not of concern, some
guidelines suggest UDT between two and four times per year on a random basis (Chou et
al., 2009; Trescot et al., 2006). For those patients with non-compliant behavior or a history of
addiction, testing should be done as often as every office visit (Chou et al., 2009; Trescot et
al., 2006).
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Toxicity and Drug Testing
Edited by Prof. Bill Acree
ISBN 978-953-51-0004-1
Hard cover, 528 pages
Publisher InTech
Published online 10, February, 2012
Published in print edition February, 2012
Modern drug design and testing involves experimental in vivo and in vitro measurement of the drug
candidate's ADMET (adsorption, distribution, metabolism, elimination and toxicity) properties in the early
stages of drug discovery. Only a small percentage of the proposed drug candidates receive government
approval and reach the market place. Unfavorable pharmacokinetic properties, poor bioavailability and
efficacy, low solubility, adverse side effects and toxicity concerns account for many of the drug failures
encountered in the pharmaceutical industry. Authors from several countries have contributed chapters
detailing regulatory policies, pharmaceutical concerns and clinical practices in their respective countries with
the expectation that the open exchange of scientific results and ideas presented in this book will lead to
improved pharmaceutical products.
How to reference
In order to correctly reference this scholarly work, feel free to copy and paste the following:
Amadeo Pesce, Cameron West, Kathy Egan-City and William Clarke (2012). Diagnostic Accuracy and
Interpretation of Urine Drug Testing for Pain Patients: An Evidence-Based Approach, Toxicity and Drug
Testing, Prof. Bill Acree (Ed.), ISBN: 978-953-51-0004-1, InTech, Available from:
http://www.intechopen.com/books/toxicity-and-drug-testing/urine-drug-testing-in-pain-patients
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